1. Field of the Invention
The present invention relates to a process for the preparation of 4-oxo-1-benzopyran-2-carboxylic acid derivatives, intermediates for synthesizing the compounds, and a process for the preparation of the intermediates.
2. Related Arts
4-Oxo-1-benzopyran-2-carboxylic acid derivatives as final products of the invention are shown by the formula ##STR2## wherein X and Y are hydrogen atom, halogen atom or alkyl group, and R.sub.1 is hydrogen atom or alkyl group.
The compounds represented by Formula I have been known as intermediates for preparing pharmacologically active compounds and more particularly the following optically active 6-fluoro-2,3-dihydro-2',5'-dioxo-spiro(4H-1-benzopyran-4',4'-imidazolidine )-2-carboxamide [Jap. Pat. No. 63-57588 (A) corresponding to a part of U.S. patent application Ser. No. 90,729 filed Aug. 28, 1987 and EP-A1-0264586] which shows powerful inhibition to activity of aldose reductase enzymes and thus have been expected as an effective ingredient for medicines to cure intractable complications due to diabetes. ##STR3##
The compounds shown by the Formula I, wherein R.sub.1 is hydrogen atom have been disclosed in Jap. Pat. No. 63-250373 (A) corresponding to a part of said U.S. patent application Ser. No. 90,729 and EP-A1-0264586. According to disclosures given in the literatures, the compounds are synthesized as shown by following reaction formulae. ##STR4## (In the formulae, X and Y have the meanings as referred to, and Ph is phenyl radical)
For preparing 4-oxo-4H-1-benzopyran-2-carboxylic acid derivatives (IV), a process through a Claisen condensation reaction of 2-hydroxyacetophenone as shown by following reaction formulae has generally been utilized ["Progr. Med. Chem." Vol. 9, pages 65-116 (1973)]. ##STR5## (In the formulae, X, Y and R.sub.1 have the meanings as referred to, and Et is ethyl radical)
Further, a process for preparing 4-oxo-4H-1-benzopyran-2-carboxylic acid (IV-a), wherein phenoxyfumaric acid is subjected to ring closure reaction, in the presence of surfuric acid, as shown below has been disclosed in "Chem. Soc." Vol. 77, page 1179 (1900), but the literature does not refer to operation conditions and yield of the compound. ##STR6##
Moreover, Jap. Pat. No. 60-132977 (A) discloses 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid shown by the following formula (IV-b), but this literature does not show any process for synthesizing the compound. ##STR7##
Among the processes as referred to, the process proposed by the present inventors and disclosed in said Jap. Pat. No. 63-250373 (A) accompanies such an inconvinience in economical view point that (-)-isomer will also be prepared, in equimolecular amount, in addition to objective (+)-isomer, since the objective (+)-isomer can be prepared through an activation of the racemic 4-oxo-1-benzo-2-carboxylic acid derivative (I-a), reaction of the activated racemic compound with (S)-(-)-1-methylbenzylamine to prepare a diastereomer mixture of (S)-1-methylbenzylamides, and a optical resolution of the diastereomer mixture.
While, the process as disclosed in said "Progr. Med. Chem." Vol. 9, pages 65-116 (1973), which utilizes the Claisen condensation reaction, has such disadvantages from the view point of actual and industrial operation that anhydrous solvent is required and the raw material of 2-hydroxyacetophenone derivative is expensive.